The invention relates to a method for coating implant materials with carbonated calcium phosphate films. More in particular, it is concerned with the use of carbon dioxide gasxe2x80x94a weak acidxe2x80x94to decrease the pH of aqueous supersaturated calcifying solutions and deposit carbonate containing calcium phosphate layers onto implants during the natural release of carbon dioxide gas at physiological temperature. Furthermore, the invention describes a new coating method for improving biocompatibility and bone-bonding properties of medical implants, such as orthopedic and dental prostheses.
Calcium phosphates are the principal constituent of hard tissues like bone, cartilage, tooth enamel and dentine. Naturally occurring bone minerals are made of sub-micrometer, poorly-crystalline carbonated calcium phosphate crystals with hydroxyapatite structure. However, unlike the synthetic and ideal stoichiometric hydroxyapatite Ca10(PO4)6(OH)2 with atomic Ca/P ratio of 1.67, the composition and crystallinity of bone mineral is significantly different. Bone minerals consist mainly of a complex mixture of calcium ions, phosphate ions, carbonate ions, and hydroxyl ions and may be represented by the following formulae:
Ca8.3(PO4)4.3(HPO4,CO3)1.7(OH,CO3)0.3.xH2O 
It has been demonstrated that calcium phosphate coatings on metal implants allow a rapid bone apposition due to their osteoconductive property, as compared with bare implants, e.g. cemented-less proximal hip stems. In vivo and in contact with body fluids, a thin layer of biological hydroxyl carbonated apatite is formed on the surface of some implants, like bioactive glasses, hydroxyapatite ceramics. Subsequently, living bone tissue is directly apposite to this HCA layer. The direct bone apposition onto and/or growth into the implant surface conduct to some advantages such as a firm and immediate implant fixation and long term result.
Several techniques, such as plasma spraying, flame spraying, electrophoretic deposition, magnetron sputtering and dipping, have been developed for coating hydroxyapatite and others calcium phosphates onto implants. The most conventional coating method is plasma spraying.
A drawback of most hydroxyapatite-coated implants is that the anchoring of hydroxyapatite onto the implant requires elevated processing temperatures, which limit the choice of substrate materials and result in high processing costs. In the plasma-spraying process, the raw material i.e. hydroxyapatite, is once molten at a high temperature so that the resulting apatite coatings are different in type from bone apatite. The coatings are frequently thick and brittle and are subjected to fracture at the interface between coating and implant, e.g. between hydroxyapatite and titanium, thereby releasing large particles in the body. Moreover, the method is rather unsuitable for numbers of polymer substrates because of the high temperature involved. Furthermore, it is not possible to incorporate biologically active agents, like proteins or antibiotics, within the coating, which may be useful to encourage bone in-growth or to prevent infection.
Additionally, most of these coatings are produced in a line of sight process, thereby prohibiting uniform application of hydroxyapatite on implants with complex surface geometry (e.g. porous surface). The previous methods have low efficiency for small and round-shaped substrates such as metallic dental implants.
The aim of the present invention is to provide a simple method for coating an implantable device with a thin, dense and bioactive layer of carbonated calcium phosphate. The said layers are processed at ambient temperature by soaking the implantable devices into a calcifying solution where carbon dioxide gas is passed through. The produced bioactive coatings result in effective bone apposition and in-growth and thereby ensure bone-bonding properties to the implants. The implantable device can be used in a wide variety of biomedical applications (surgery, bone-replacement, prosthodontics, dental roots, crowns and orthopedic joints, etc).
The solubility products of the different calcium carbonate phosphate compounds are described as a function of pH, carbon dioxide partial pressure and temperature in the publication of G. Vereecke and J. Lemaitre, xe2x80x9cCalculation of the solubility diagrams in the system Ca(OH)2xe2x80x94H3PO4xe2x80x94KOHxe2x80x94HNO3xe2x80x94CO2xe2x80x94H2Oxe2x80x9d J. Crystal Growth 104 (1990) 820-832 and in the contribution of F. C. M. Driessens entitled xe2x80x9cFormation and stability of calcium phosphates in relation to phase composition of the mineral of calcified tissuexe2x80x9d in Calcium Phosphate Bioceramics, edited by K. de Groot, CRC Press (1984).
The publication of P. Serekian entitled xe2x80x9cHydroxyapatite coatings in othopaedic surgeryxe2x80x9d edited by R. G. T. Geesink and M. T. Manley, Raven Press Ltd, New York (1993), p 81-97, discusses the advantages and drawbacks of plasma and flame spraying, electrophoresis, dip coating and magnetron sputtering.
EP No. 0 389 713 B1 (Kokubo, 1989) describes a process for applying a bioactive hydroxyapatite film on implant substrates of inorganic, metallic or organic material, by soaking an assembly comprising a glass, mainly comprising CaO and SiO2, facing a substrate at a predetermined distance apart, in an aqueous solution substantially saturated or supersaturated with constituent ions of hydroxyapatite. In the method according to the present invention, it is not necessary to provide an assembly of glass facing the substrate to be coated.
EP No. 0 450 939 A2 and corresponding U.S. Pat. Nos. 5,164,187 and 5,188,670 (Norian, 1990,1991) describe a complicated process and apparatus for coating porous substrates with a hydroxyapatite film. This method comprises combining a soluble calcium ion source and a soluble phosphate ion source, wherein the molarity of the calcium ions is in the range of about 0.05-5 M, the molarity of the phosphate ions is in the range of about 0.01-1 M, at the temperature of 60-90xc2x0 C. and pH of 5-8.5, under conditions leading to controlled nucleation and modulated growth of hydroxyapatite needle-like crystals. Basically, one solution is injected into a circulating medium, resulting in the precipitation of hydroxyapatite whiskers or single-crystals that reach and cover the surface to be coated. This prior art method has two important drawbacks. First, hydroxyapatite crystals precipitate in the solution. On the opposite, in the method according to the invention, crystals nucleate directly on the implant surface leading to superior interfacial attachment. Second, the coating, as described in the above process, is made by stacking hydroxypatite crystals through a fluid stream which is essentially a line of sight process and thereby giving shadows effects on complex shaped surfaces. In the present invention, the deposition of carbonated calcium phosphate layers is not dependent on the direction of fluid flow.
International patent application WO A,93 07912 (Sherwood Medical, 1993) describes a bioimplant obtained by soaking a base material to be coated in a saturated or supersaturated solution of hydroxyapatite. The base material has been previously provided with an organic polymer containing sulfonic or carboxyl groups. In the method according to the invention, it is not necessary to first provide the implant to be coated with such an organic coating.
International patent application WO 95 13101 (de Groot, 1993) teaches a method for coating an implant substrate with a bioactive material represented by the general formula Cap (PO4)q(CO3)r(OH)s in which p greater than 1 and q, r and s greater than 0, and in which 2p=3q+2r+s. The said substrate is soaked in a solution in which at least calcium ions, preferably carbonate ions, and if required, phosphate ions are present, after which the bioactive material is precipitated from the solution on the substrate by either heating the solution or the substrate. In the present invention, the temperature is fixed within the range 5-50xc2x0 C. and there is no need to heat the solution or the substrate to induce the precipitation of calcium phosphate. Moreover, the feasibility and bioactivity of such a coating has not been experimentally demonstrated in the International Patent Application WO 95 13101.
EP No. 0 678 300 A1 (Kokubo, 1994) discloses a process for producing a bone substitute material. In essence, a primary surface layer of a titanium oxide phase and amorphous phases of alkali titanates are formed by soaking a base material made of titanium or its alloy in an alkali solution and heating the base material to temperature lower than the transition point e.g. 300-800xc2x0 C. Subsequently, the alkali- and heat-treated base material is immersed in aqueous solution which contains calcium and phosphorus ions to a level of, at least the apatite solubility, and thus producing a second layer comprising apatite on top of the said primary surface layer.
The patent applications EP 972011425/2, U.S. Pat. No. 8,855,835 and Canada 2,205,107 (Isotis BV) describe a nanotechnology process for implant surface treatment which can subsequently induce the precipitation of calcium phosphate layers by soaking in a calcifying solution. The implantable devices have a surface roughness before coating with an average peak distance between 10 and 1000 nm to induce the precipitation of calcium phosphate layers.
Japanese patent application 08040711 discloses a process for forming a hydroxy apatite coating, wherein calcium phosphate is dissolved in a solution containing sodium hydroxide, by applying high pressure carbon dioxide gas. The coating is deposited by discharge of carbon dioxide gas. In this known process, sodium hydroxide is present in the calcifying solution, which significantly increases the pH. As a result, a high pressure of carbon dioxide is needed in order to obtain a low enough pH to dissolve sufficient calcium phosphate.
The object of the present invention is to provide a simple method for coating the surface of medical implants with bioactive carbonated calcium phosphate layers. The said coatings are produced by soaking the implantable devices into highly concentrated calcifying solutions at low temperature. The calcifying solutions are composed of calcium, phosphate, magnesium, carbonate and additionally sodium chloride salts dissolved into water by bubbling carbon dioxide gas. During the natural release of carbon dioxide gas or its exchange with air, the pH of the calcifying solution is increased and the saturation is raised until the nucleation of carbonated calcium phosphate crystals on the surface of implantable devices. The said layer deposited and growth onto the medical implants. The process of bubbling/releasing CO2 gas through or from calcifying solutions can be repeated until a sufficient thickness has been reached. The present invention has the following advantages over conventional coating techniques: it is simple and cost-effective approach, no expensive and intricate pieces of equipment are needed. It is a low temperature process applicable to various substrates. Further, it has been found that materials can be deposited on a substrate in the present process, which was hitherto impossible. Octacalcium phosphate coatings, for instance, cannot be prepared with conventional plasma spraying techniques, due to the heat instability of the coating material. Such coatings also have been found not to grow in epitaxial fashion when employing other coating techniques.
As the coating is applied by using a fluid, complex shaped implants (porous or beaded surfaces) can be uniformly covered with a thin layer of carbonated calcium phosphate. The obtained layer is strong and wear resistant. The said layer is formed by using a biomimetic approach (physiological fluids, temperature and pH) and thus, a bone-like apatite layer having a high reactivity and adsorption property is deposited on the surface of medical implants. The biocompatibilty and bone-bonding properties of such coated devices have been demonstrated by implantation in animal models.